Attenuating the Oxidative and Myocardial Toxicity of Polymerized Hemoglobins

减轻聚合血红蛋白的氧化和心肌毒性

• 批准号: 8916214
• 负责人: Pedro Cabrales
• 金额: $ 39.98万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-11 至 2017-03-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8916214
• 关键词: Accounting; Adverse effects; Adverse reactions; Animal Model; Animals; Antioxidants; Area; Attenuated; Blood; Blood Vessels; Blood Volume; Cardiac; Carrying Capacities; Cattle; Cavia; Cells; Chemicals; Chemistry; Cholesterol; Clinical; Clinical Trials; Deposition; Development; Diffusion; Emerging Communicable Diseases; Endothelial Cells; Endothelium; Erythrocytes; Event; Experimental Animal Model; Extravasation; Glutaral; Health; Heme; Hemoglobin; Human; Hypertension; Incidence; Infusion procedures; Intercellular Junctions; Iron; Laboratories; Lead; Light; Lipids; Medicine; Methemoglobin; Modification; Myocardial; Myocardial Infarction; Nitric Oxide; Nucleic Acids; Organ; Oxidation-Reduction; Oxidative Stress; Oxygen; Permeability; Phase III Clinical Trials; Physiological; Population; Prevention; Property; Prosthesis; Proteins; Regulation; Relaxation; Risk; Role; Safety; Signal Transduction; Smooth Muscle Myocytes; Solutions; Staging; Surface; Testing; Therapeutic; Tissues; Toxic effect; Toxicokinetics; Transfusion; Translating; Vascular blood supply; Vascular resistance; Work; base; biophysical techniques; design; endothelial dysfunction; feeding; hypertensive heart disease; improved; innovation; molecular carrier; molecular size; novel; oxidation; oxidative damage; polymerization; prevent; response; theories; vasoconstriction

DESCRIPTION: Hemoglobin (Hb)-based oxygen (O2) carriers (HBOCs) are currently being developed as red blood cell (RBC) substitutes for use in transfusion medicine. Despite significant commercial development, recent late stage clinical results of polymerized hemoglobin (PolyHb) solutions (i.e. Hemopure� (OPK Biotech, Cambridge, MA), a glutaraldehyde polymerized bovine Hb; and PolyHeme� (Northfield Laboratories Inc., Evanston, IL), a glutaraldehyde polymerized pyridoxylated human Hb) hamper further development. Both of these commercial products elicit vasoconstriction at the microcirculatory level, and lead to the development of systemic hypertension and oxidative tissue damage. These side-effects are hypothesized to occur either by a nitric oxide (NO) scavenging or oxygen (O2) oversupply mechanism and are both exacerbated by PolyHb extravasation into the tissue space. In light of these 2 potential mechanisms, it is apparent that PolyHb size will have a profound impact on the extent of vasoconstriction, systemic hypertension and oxidative tissue toxicity. Since, increasing the size of the HBOC will prevent its extravasation through endothelial cell-cell junctions, decreasing the magnitude of the HBOC diffusion coefficient and thus decreasing both the extent of NO scavenging and hyper-oxygenation of the blood vessel wall. Using this simple approach, our team demonstrated that increasing the molecular size of PolyHb eliminated vasoconstriction and hypertension in two different animal species. Prevention of HBOC extravasation should also decrease ROS-induced tissue oxidative damage by preventing the HBOC from coming into intimate contact with tissues. Therefore in this application, we hypothesize that HBOC size will regulate oxidative damage to tissues and organs as well as myocardial function. In order to test the central hypothesis of this application, we propose 2 specific aims: Specific Aim 1: Analyze the role of endothelial function on PolyHb toxicokinetics. Specific Aim 2: Analyze the role of PolyHb on myocardial function. The proposed work is both significant and innovative, since it seeks to develop safe and efficacious PolyHbs for use in transfusion medicine. In addition, state-of-the-art biophysical techniques and two unique animal models will be used to understand PolyHb physiological responses and determine the clinical potential of these novel materials.

描述：基于血红蛋白(Hb)的氧(O2)载体(HBOC)目前正被开发为用于输血医学的红细胞(RBC)替代品。尽管有重大的商业开发，但聚合血红蛋白(PolyHb)溶液(即血液�(OPK Biotech，马萨诸塞州剑桥)和Polyheme�(诺斯菲尔德实验室公司，伊文斯顿，伊利诺伊州)，一种戊二醛聚合的人Hb)最近的后期临床结果阻碍了进一步的开发。这两种商业产品都在微循环水平上引起血管收缩，并导致全身高血压和氧化组织损伤的发展。这些副作用被认为是通过一氧化氮(NO)清除或氧气(O2)供应过剩机制发生的，并因PolyHb渗入组织间隙而加剧。根据这两种可能的机制，显然，PolyHb的大小将对血管收缩、全身性高血压和氧化组织毒性的程度产生深远的影响。因为，增加HBOC的大小将防止其通过内皮细胞-细胞连接外溢，从而降低HBOC扩散系数的大小，从而降低血管壁的NO清除和高氧程度。使用这种简单的方法，我们的团队证明了增加PolyHb的分子大小可以消除两种不同动物的血管收缩和高血压。防止HBOC外渗还应通过防止HBOC与组织的亲密接触来减少ROS引起的组织氧化损伤。因此，在这一应用中，我们假设HBOC大小将调节组织和器官的氧化损伤以及心肌功能。为了验证这一应用的中心假设，我们提出了两个具体目标：具体目标1：分析内皮功能在PolyHb毒代动力学中的作用。具体目的2：分析PolyHb对心肌功能的影响。这项拟议的工作具有重大意义和创新性，因为它寻求开发用于输血医学的安全和有效的聚Hbs。此外，还将使用最先进的生物物理技术和两个独特的动物模型来了解PolyHb的生理反应，并确定这些新材料的临床潜力。

项目成果

Mixtures of tense and relaxed state polymerized human hemoglobin regulate oxygen affinity and tissue construct oxygenation.

• DOI: 10.1371/journal.pone.0185988
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Belcher DA;Banerjee U;Baehr CM;Richardson KE;Cabrales P;Berthiaume F;Palmer AF
• 通讯作者: Palmer AF

Oxygen transport during hemodilution with a perfluorocarbon-based oxygen carrier: effect of altitude and hyperoxia.

使用基于全氟化碳的氧载体进行血液稀释期间的氧气输送：海拔和高氧的影响。

• DOI: 10.1152/japplphysiol.00152.2008
• 发表时间: 2008
• 期刊: Journal of applied physiology (Bethesda, Md. : 1985)
• 作者: Gardeazábal,Tatiana;Cabrera,Mariana;Cabrales,Pedro;Intaglietta,Marcos;Briceño,JuanCarlos
• 通讯作者: Briceño,JuanCarlos

Turning on the Radio: Epigenetic Inhibitors as Potential Radiopriming Agents.

• DOI: 10.3390/biom6030032
• 发表时间: 2016-07-04
• 期刊: Biomolecules
• 影响因子: 5.5
• 作者: Oronsky B;Scicinski J;Kim MM;Cabrales P;Salacz ME;Carter CA;Oronsky N;Lybeck H;Lybeck M;Larson C;Reid TR;Oronsky A
• 通讯作者: Oronsky A

Cardioprotective Effect of Phase 3 Clinical Anticancer Agent, RRx-001, in Doxorubicin-Induced Acute Cardiotoxicity in Mice.

• DOI: 10.1021/acs.molpharmaceut.9b00150
• 发表时间: 2019-04
• 期刊: Molecular pharmaceutics
• 影响因子: 4.9
• 作者: B. Oronsky;Eilleen S. Y. Ao-ieong;O. Yalcin;C. Carter;P. Cabrales